Severe agranulocytosis in patient with Graves’ disease on second exposure to carbimazole

Abstract

Summary

For half a century, antithyroid drugs (ATDs) have been the first-line treatment for Graves’ disease. ATDs, e.g. carbimazole, are associated with minor and serious adverse effects. These include rash, urticaria, arthralgia, hepatotoxicity, vasculitis, and agranulocytosis. Agranulocytosis is a potentially serious adverse effect characterised by a neutrophil count <0.5 × 10⁹ cells/L, which may deteriorate further into sepsis and death. This is a case report of a 47-year-old female who had a 17-year history of Graves’ disease. She received carbimazole for 2 years, which was stopped after remission. She presented with relapsed thyrotoxicosis in 2025 when carbimazole (40 mg) was reinstituted. Three weeks later, the patient self-presented to the hospital with sore throat, painful swallowing, and sweating. Examination found oral ulceration, pharyngeal erythema, and tender cervical lymphadenopathy. She was admitted to the hospital and treated under the endocrinology team as agranulocytosis, carbimazole was stopped, and she was treated per local guidelines of neutropenic sepsis. After agranulocytosis was resolved, the patient underwent total thyroidectomy. Despite being well-tolerated, doctors and patients should be well aware of this potentially serious adverse effect of carbimazole.

Learning points

• Antithyroid drugs (ATDs) are rarely associated with agranulocytosis.

• ATD-induced agranulocytosis is regarded as a serious life-threatening emergency.

• The only option for the management of patients with Graves’ disease-developed agranulocytosis is surgery.

• Educating the patients regarding the symptoms of agranulocytosis is vital for saving their life.

• ATD-induced agranulocytosis can happen long time after exposure or even after second exposure to these drugs.

Background

Graves’ disease is an autoimmune disorder in which TSH receptor antibodies (TRAbs) stimulate the TSH receptor in the thyroid gland, resulting in a hyperthyroid state (1). Graves’ disease is regarded as the most common cause of hyperthyroidism in women (1). Currently, there are three modalities used to treat Graves’ disease, including antithyroid drugs (ATDs), radioactive iodine therapy, or thyroidectomy (2). For half a century, ATDs have been the first-line therapy (2). Most common ATDs include methimazole, which is an effective drug with the longest half-life; carbimazole, which is a pro-drug as it is converted to methimazole following absorption; and propylthiouracil (2).

ATDs inhibit the synthesis of thyroxine in the thyroid gland by blocking the thyroperoxidase enzyme. Moreover, propylthiouracil, in addition to blocking thyroperoxidase, partially inhibit the peripheral conversion of T4 to T3 (3). ATDs are associated with minor and more serious major side effects (3). Minor side effects include urticaria, macular rash, arthralgia, and gastrointestinal upset. Serious side effects include agranulocytosis, hepatotoxicity, and vasculitis (4).

Agranulocytosis is a rare serious adverse effect of drugs characterised by a decrease in peripheral neutrophil count to <0.5 × 10⁹ cells/L (5). The mortality rate for non-chemotherapy-induced agranulocytosis is 9.68% based on reports from 2004 to 2024 (6). High-risk factors for mortality in patients with agranulocytosis include advanced age (over 65 years), renal insufficiency (serum creatinine level: >120 μmol/L), and the presence of bacteraemia or shock (6).

Case presentation

A 47-year-old female with a medical history of migraine, hypertension, polycystic ovarian syndrome, and venous thromboembolism was diagnosed with hyperthyroidism 17 years ago and went into remission after a two-year course of carbimazole.

Seventeen years later, the patient presented with symptoms and signs of recurrent hyperthyroidism. Her thyroid function test (TFT) showed a thyroid-stimulating hormone (TSH) level of 0.06 mIU/L (reference range (RR): 0.4–5.0 mIU/L), a free thyroxine (fT4) level of 82.1 pmol/L (RR: 10–25 pmol/L), and a free triiodothyronine (fT3) level of 30.8 pmol/L (RR: 3.5–7.8 pmol/L). Carbimazole was reinstituted with a dose of 40 mg daily, in addition to propranolol 80 mg daily. The patient was advised to return if she had fever or sore throat as part of the clinic discussion to make the patient aware of the possible side effects of carbimazole, particularly agranulocytosis.

Twenty days after starting carbimazole, the patient presented with a 3-day history of sore throat, odynophagia, and night sweats. Examination revealed ulceration on the lips and hard palate with pharyngeal erythema. There was tender cervical lymphadenopathy in the left anterior triangle of the neck. Chest and abdominal examinations were normal. She was apyrexial (37.1°C) with normal vital signs.

Investigations

The patient’s blood investigations were as follows: WBC: 2.6 × 10⁹/L (RR: 4–11); Hb: 138 g/L (RR: 115–160); RBC: 5.01 × 10¹²/L (RR: 3.8–5.8); HCT: 0.42 L/L (RR: 0.37–0.47); MCV: 83.1 fl (RR: 77–98); MCH: 27.5 pg (RR: 27.5–32.5); RDW: 13.6% (RR: 10.9–15.7); platelets: 219 × 10⁹/L (RR: 150–400); and neutrophil count: 0.1 × 10⁹/L. Her blood investigation progression over the following days is demonstrated in Table 1.

Table 1.

TFTs and blood indices of the patient over the period of admission.

	Day 1	Day 3	Day 6	Day 10	Day 12	Day 16	Day 17	Day 18	Day 19	Day 20	Day 21
TSH (mIU/L)	0.08	0.08	0.09	0.12	0.1	0.14	0.1	0.1	0.1	0.12	0.14
fT3 (pmol/L)			18.2	21.3	23.4	12.3	8.1	6.5	5.9	4.6	4.3
fT4 (pmol/L)	38.5	48.1	56.5	64	52.8	59.2	50.8	39.4	25.2	30	23.3
WBCs (×109/L)	2.5	1	3.4	5.5	5.8	15.6	11.5	12.1	16.4	14.9	9.7
Neutrophils (×109/L)	0	0.1	1.1	3.3	3.5	7.1	7.3	9	8	7	7.9
Lymph (×109/L)	1.7	0.8	1.9	1.8	1.9	7	3.6	2.6	7.1	6.7	1.6
Eosinophils (×109/L)	0.1	0	0	0.1	0.1	0.1	0	0	0.1	0.1	0
Hb (g/L)	139	130	134	139	141	148	135	142	139	135	136
CRP (mg/L)	38	6	4.9	17	4.9	4.9	4.9	4.9	4.9	4.9	4.9

TFTs, thyroid function tests.

Treatment

The patient was admitted to the hospital in protective isolation, carbimazole was stopped, and she was treated as per neutropenic sepsis local hospital guidelines. Septic screen, including CXR, US neck, and respiratory PCR, did not reveal any abnormality. After discussing with the haematology team and due to a spontaneous improvement in neutrophil count after withholding carbimazole, the patient did not need administration of filgrastim (granulocyte colony-stimulating factor). The following drugs were prescribed: piperacillin/tazobactam, gentamicin, and acyclovir. Importantly, the patient was started on oral cholestyramine 4 g QDS to reduce the absorption of thyroxine from the portal circulation and received hydrocortisone 100 mg intravenously three times daily for 3 days followed by 40 mg oral prednisolone to reduce the conversion of fT4 to fT3 (7). Propranolol dose was doubled to control the thyrotoxic symptoms aiming for the heart rate to be less than 100/minute. A proton pump inhibitor was initiated for gastric protection. Full blood count was monitored daily, and her neutrophil count normalised after 7 days, following which the antibiotics were stopped (Fig. 1).

Figure 1.

Neutrophil counts of the patient over the period she was admitted to the hospital with agranulocytosis.

During the admission, she had transient leucocytosis (likely steroid-induced) and complained of severe headache, neck pain, and high blood pressure (BP). Her BP was optimised with the addition of amlodipine. Neurological examination and CT head were unremarkable. She improved with non-steroidal anti-inflammatory drugs. In view of the risk of further agranulocytosis with ATDs, the decision after discussion with the patient was to proceed for total thyroidectomy.

Outcome and follow-up

To achieve preoperative control of thyrotoxicosis, and with close liaison with the thyroid surgeon, we started the patient on Lugol’s iodine 7 drops TDS orally for exactly 7 days prior to the surgery (to benefit from the Wolf–Chaikoff effect), which succeeded in normalising fT3, and the patient had uneventful thyroidectomy after about 3 weeks of presenting with agranulocytosis. Levothyroxine was started, and prednisolone was tapered. We noticed that both cholestyramine and steroids did not make a large reduction in free thyroid hormones concentration in comparison with Lugol’s iodine (Fig. 2).

Figure 2.

Relationship of the concentration of free T3 and T4 hormones with the administration of various management modalities in our patient.

Discussion

Approximately 70–97% of agranulocytosis cases are caused by medications (6). Carbimazole-induced agranulocytosis is a rare but serious complication of ATDs. The first case of agranulocytosis caused by ATDs was reported in 1952. In that year, the first case of death was also reported in patient who developed high fever and dyspnoea and eventually died of pneumonia (4).

The reported incidence of this condition is 0.1–0.5%. It usually develops within the first 90 days of treatment (8). Agranulocytosis is more likely with the use of high doses of carbimazole (>30 mg), female sex, and older patients (8). An absolute neutrophil count of less than 0.1 × 10⁹ cells/L is associated with a high risk of infections, sepsis, and mortality than those higher than 0.1 × 10⁹ cells/L (5).

There are two mechanisms that explain carbimazole-induced agranulocytosis. The first mechanism is direct toxicity due to the oxidative stress metabolites produced by myeloperoxidase and cytochrome P450 enzymes, which leads to apoptosis of neutrophils (4). The other mechanism is immune mediated, involving the antineutrophilic cytoplasmic antibodies. Studies have shown anti-granulocyte antibodies by immunofluorescence and cytotoxic assays in patients with ATD-induced agranulocytosis (3). Antigen targets (proteinase 3) are expressed on the surface of neutrophils; therefore, antineutrophilic cytoplasmic antibodies may have a role in the pathogenesis of agranulocytosis (3).

Routine monitoring of neutrophil count in patients receiving ATDs is considered not cost-effective (3). This view has been challenged by literature reports of asymptomatic patients who were found to have agranulocytosis (3). The best practice that may save the lives of patients with agranulocytosis is education regarding the symptoms and signs of agranulocytosis and the importance of presenting to health services immediately after noticing such symptoms (9). Our patient was educated regarding the symptoms and signs of agranulocytosis, which helped earlier diagnosis and effective treatment of her condition.

Importantly, we should emphasise the fact that our patient develops agranulocytosis on second exposure to carbimazole. Unfortunately, the patient did not remember the previous dose on her first thyrotoxicosis attack 17 years ago. Cooper reported that it is possible to develop agranulocytosis on second exposure to carbimazole (3). Moreover, leucopenia is regarded as a common side effect of carbimazole; however, serious neutropenia is a rare and serious adverse effect that needs an immediate action (10).

Radioactive iodine therapy was not an option in the definitive management of this case because prior to radioactive iodine, we need to stabilise the thyroid gland toxicity using the only option we have, which is Lugol’s iodine for 7–10 days. The administration of Lugol’s iodine will cause the saturation of the thyroid gland with iodine; therefore, the later administration of radioactive iodine will be ineffective due to already iodine-saturated gland.

Conclusion

Carbimazole is a well-tolerated readily available drug that is widely used for the treatment of hyperthyroidism. However, clinicians should be aware and should not underestimate the rare but life-threatening adverse effects of its use. Patient should be given written and verbal information regarding serious adverse effects that may follow the use of carbimazole. In the event of agranulocytosis, stopping ATD therapy immediately and implementing the treatment for neutropenic sepsis is required. Following normalisation of neutrophil count, alternative method of controlling thyrotoxicosis other than ATDs should be pursued, such as radioactive iodine or total thyroidectomy.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent was obtained from the patient for publication of this case report.

Author contribution statement

All authors contributed to the management of the patient. All authors contributed to writing the case report.